Crystal structure of staphylococcal enterotoxin I (SEI) in complex with a human major histocompatibility complex class II molecule.

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TitleCrystal structure of staphylococcal enterotoxin I (SEI) in complex with a human major histocompatibility complex class II molecule.
Publication TypeJournal Article
Year of Publication2006
AuthorsFernández, MM, Guan, R, Swaminathan, CP, Malchiodi, EL, Mariuzza, RA
JournalJ Biol Chem
Volume281
Issue35
Pagination25356-64
Date Published2006 Sep 1
ISSN0021-9258
KeywordsAmino Acid Sequence, Binding Sites, Crystallography, X-Ray, Enterotoxins, Hemagglutinins, HLA-DR1 Antigen, Humans, Inflammation, Ions, Major Histocompatibility Complex, Models, Molecular, Molecular Sequence Data, Peptides, Protein Binding, Protein Conformation, Sequence Homology, Amino Acid, Superantigens, Zinc
Abstract

Superantigens are bacterial or viral proteins that elicit massive T cell activation through simultaneous binding to major histocompatibility complex (MHC) class II and T cell receptors. This activation results in uncontrolled release of inflammatory cytokines, causing toxic shock. A remarkable property of superantigens, which distinguishes them from T cell receptors, is their ability to interact with multiple MHC class II alleles independently of MHC-bound peptide. Previous crystallographic studies have shown that staphylococcal and streptococcal superantigens belonging to the zinc family bind to a high affinity site on the class II beta-chain. However, the basis for promiscuous MHC recognition by zinc-dependent superantigens is not obvious, because the beta-chain is polymorphic and the MHC-bound peptide forms part of the binding interface. To understand how zinc-dependent superantigens recognize MHC, we determined the crystal structure, at 2.0 A resolution, of staphylococcal enterotoxin I bound to the human class II molecule HLA-DR1 bearing a peptide from influenza hemagglutinin. Interactions between the superantigen and DR1 beta-chain are mediated by a zinc ion, and 22% of the buried surface of peptide.MHC is contributed by the peptide. Comparison of the staphylococcal enterotoxin I.peptide.DR1 structure with ones determined previously revealed that zinc-dependent superantigens achieve promiscuous binding to MHC by targeting conservatively substituted residues of the polymorphic beta-chain. Additionally, these superantigens circumvent peptide specificity by engaging MHC-bound peptides at their conformationally conserved N-terminal regions while minimizing sequence-specific interactions with peptide residues to enhance cross-reactivity.

DOI10.1074/jbc.M603969200
Alternate JournalJ. Biol. Chem.
PubMed ID16829512
PubMed Central IDPMC2730046
Grant ListR37 AI036900-12 / AI / NIAID NIH HHS / United States